Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.1.137 (phosphatidylinositol 3-kinase)
11,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Preconditioning the heart by exposure to brief cycles of ischemia-reperfusion causes it to become very resistant to ischemia-induced infarction. This protection has been shown to depend on a large number of signal transduction components whose arrangements within the cardiomyocyte are unknown. To aid the translation of this phenomenon to the clinical setting, we have attempted to map the signal transduction pathways responsible for this protection. To resolve the signaling order we have injected a signal at an intermediate point in the system transduction pathway and monitored it at a downstream site. System analysis reveals both parallel and series signaling arrangements. Separate trigger and mediator phases could be identified. The trigger phase is now well mapped. During the preconditioning ischemia, autacoids--including adenosine, opioids, and bradykinin--are released from the heart. These substances occupy their respective Gi-coupled receptors. Opioid and bradykinin receptors activate phosphatidylinositol 3-kinase (PI3-kinase) which, through phosphoinositide-dependent protein kinase, causes activation of Akt. Opioid couples through transactivation of the epidermal growth factor receptor, while bradykinin's coupling to PI3-kinase is unknown. PI3-kinase causes extracellular signal regulated kinase (ERK)-dependent activation of endothelial nitric oxide synthase. The resulting nitric oxide activates soluble guanylyl cyclase resulting in cyclic C-GMP-dependent protein kinase (PKG) activation through production of cyclic guanosine monophosphate. PKG initiates opening of ATP-sensitive potassium channels on the inner membrane of the mitochondria. Potassium entry into mitochondria causes the generation of free radicals during reperfusion when oxygen is reintroduced. Through redox signaling, these radicals activate protein kinase C (PKC) and put the heart into the protected phenotype that persists for one to two hours. Although adenosine receptors activate PI3-kinase, they also have a second direct coupling to PKC and thus bypass the mitochondrial pathway. The mediator phase occurs during the first minutes of reperfusion following the lethal ischemic insult and is still poorly defined. Briefly, PKC somehow potentiates adenosine's ability to activate signaling from low-affinity A(2b) adenosine receptors. These receptors couple to the survival kinases, Akt and ERK, believed to inhibit the formation of deadly mitochondrial permeability transition pores through the phosphorylation of glycogen synthase kinase-3beta. The proposed signaling maps reveal many points at which drugs can trigger the protected phenotype.
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PMID:Mapping preconditioning's signaling pathways: an engineering approach. 1837 91

Morphine has been shown to protect the myocardium against ischemia-reperfusion injury through inhibition of glycogen synthase kinase-3beta (GSK-3beta). Given that GSK-3beta is known to modulate the mitochondrial permeability transition pore (mPTP), we investigated the role of mPTP in the cardioprotective effect of morphine and the GSK-3beta inhibitor SB216763 [SB; 3-(2,4-dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione] during ischemia-reperfusion. Both morphine (0.3 mg/kg) and SB (0.6 mg/kg) reduced infarct size in a model of regional myocardial ischemia-reperfusion in rats (13 +/- 1 and 14 +/- 3% of the area at risk versus 33 +/- 4% in controls; p < 0.05). Morphine and SB protected the ischemic myocardium against Ca(2+)-induced mPTP opening as demonstrated by the increased capacity of mitochondria to retain Ca(2+) when they were isolated from the ischemic zone 10 min after the onset of reperfusion (59 +/- 8 and 66 +/- 3 versus 29.5 +/- 6 nmol Ca(2+)/mg x protein, respectively; p < 0.05). This was associated with a restoration of mitochondrial oxidative phosphorylation parameters. In isolated adult rat cardiomyocytes subjected to anoxia-reoxygenation, morphine (2 microM), SB (3 microM), and the direct mPTP inhibitor cyclosporine A (3 microM) delayed mPTP opening as assessed by the calcein loading Co(2+)-quenching technique. This was accompanied by an increase in cell survival as measured by nuclear staining with propidium iodide. These in vitro effects of morphine on inhibition of mPTP opening during anoxia-reoxygenation were suppressed by the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor wortmannin (0.1 microM). These data indicate that the infarct-limiting effect of morphine and SB is linked by a cause-effect relationship, which leads to an increased mitochondrial resistance and inhibition of mPTP opening through the PI3-kinase pathway and subsequent inactivation of GSK-3beta.
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PMID:Cardioprotective effect of morphine and a blocker of glycogen synthase kinase 3 beta, SB216763 [3-(2,4-dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione], via inhibition of the mitochondrial permeability transition pore. 1843 87

Heat stress (HS)-induced cardioprotection is associated with increased paxillin localization to the membrane fraction of neonatal rat ventricular myocytes (NRVM). The purpose of this study was 1) to examine the subcellular signaling pathways activated by HS; 2) to determine whether myocardial stress organizes and activates an integrated survival pathway; and 3) to investigate potential downstream cytoprotective proteins activated by HS. After HS, NRVM were subjected to chemical inhibitors (CI) designed to simulate ischemia by inhibiting both glycolysis and mitochondrial respiration. Protein kinase B (AKT) expression (wild type) was increased selectively with an adenoviral vector. Cell signaling was analyzed with Western blot analysis, while oncosis/apoptosis was assayed by measuring Trypan blue exclusion and/or terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining, respectively. HS increased phosphorylation of focal adhesion kinase (FAK) at tyrosine 397 but did not adversely affect the viability of NRVM before CI. HS increased association between FAK and phosphatidylinositol 3-kinase as well as causing a significant increase in AKT activity. Increased expression of wild-type AKT protected myocytes from both oncotic and apoptotic cell death. Increased expression of a FAK inhibitor, FRNK, reduced AKT phosphorylation in response to HS both at time 0 and after 10 min of CI compared with myocytes expressing empty virus. We conclude that myocardial stress activates cytoskeleton-based signaling pathways that are associated with protection from lethal cell injury.
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PMID:Heat stress activates AKT via focal adhesion kinase-mediated pathway in neonatal rat ventricular myocytes. 1853 55

Ischemic postconditioning is defined as a repetitive series of brief interruptions of reperfusion applied immediately after ischemia. In this study, postconditioning was investigated by first exposing rat organotypic hippocampal slices to 30min oxygen-glucose deprivation (OGD), which promotes selective CA1 pyramidal cell death, and 5min later to either a brief period (3min) of OGD or to a low dose (10microM) of 3,5-dihydroxyphenylglycine (DHPG) for 30min. Both protocols attenuated CA1 neuronal injury, as revealed 24h later by measuring the intensity of propidium iodide fluorescence in this region. The beneficial effects were observed when DHPG postconditioning was applied up to 15min after OGD, but not at later time points, and was not additive with the neuroprotective effects of a preconditioning DHPG treatment. The attenuation of the OGD-induced CA1 injury evoked by postconditioning was prevented when mGlu1 and mGlu5 receptor antagonists and inhibitors of phosphatidylinositol 3-kinase and Akt activity were present in the incubation medium during the 5min recovery period after OGD and the 30min exposure to DHPG. The PI3K inhibitor was also able to prevent the reduction of NMDA toxicity induced by the DHPG treatment. Finally, DHPG increased the phosphorylation of Akt in a transient and mGlu1/mGlu5-dependent manner. Our results show that activation of the mGlu1/mGlu5-PI3K-Akt signaling pathway plays a crucial role in the mechanisms of postconditioning evoked by DHPG and point to this strategy as a possible novel therapeutic tool for stroke and cerebral ischemia.
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PMID:Neuroprotection by group I mGlu receptors in a rat hippocampal slice model of cerebral ischemia is associated with the PI3K-Akt signaling pathway: a novel postconditioning strategy? 1860 74

Although neurogenesis in the hippocampus is critical for improvement of depressive behaviors and cognitive functions in neurodegeneration disorders, there is no therapeutic agent available to promote neurogenesis in adult brain following brain ischemic injury. Here we found that i.p. administration of bis(1-oxy-2-pyridinethiolato)oxovanadium(IV) [VO(OPT)], which stimulates phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal regulated kinase (ERK) pathways, markedly enhanced brain ischemia-induced neurogenesis in the subgranular zone (SGZ) of the mouse hippocampus. VO(OPT) treatment enhanced not only the number of proliferating cells but also migration of neuroblasts. VO(OPT)-induced neurogenesis was associated with Akt and ERK activation in neural precursors in the SGZ. Likewise, VO(OPT)-induced neurogenesis was blocked by both PI3K/Akt and mitogen-activated protein kinase/extracellular signal regulated kinase kinase (MEK)/ERK inhibitors. VO(OPT) treatment rescued decreased phosphorylation of glycogen synthesis kinase 3beta (GSK-3beta) at Ser-9. Finally, amelioration of cognitive dysfunction seen following brain ischemia was positively correlated with VO(OPT)-induced neurogenesis. Taken together, VO(OPT) is a potential therapeutic agent that enhances ischemia-induced neurogenesis through PI3K/Akt and ERK activation, thereby improving memory and cognitive deficits following brain ischemia.
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PMID:Bis(1-oxy-2-pyridinethiolato)oxovanadium(IV) enhances neurogenesis via phosphatidylinositol 3-kinase/Akt and extracellular signal regulated kinase activation in the hippocampal subgranular zone after mouse focal cerebral ischemia. 1861 90

The purpose of this study was to determine whether exogenous zinc prevents cardiac reperfusion injury by targeting the mitochondrial permeability transition pore (mPTP) via glycogen synthase kinase-3beta (GSK-3beta). The treatment of cardiac H9c2 cells with ZnCl2 (10 microM) in the presence of zinc ionophore pyrithione for 20 min significantly enhanced GSK-3beta phosphorylation at Ser9, indicating that exogenous zinc can inactivate GSK-3beta in H9c2 cells. The effect of zinc on GSK-3beta activity was blocked by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY-294002 but not by the mammalian target of rapamycin (mTOR) inhibitor rapamycin or the PKC inhibitor chelerythrine, implying that PI3K but not mTOR or PKC accounts for the action of zinc. In support of this interpretation, zinc induced a significant increase in Akt but not mTOR phosphorylation. Further experiments found that zinc also increased mitochondrial GSK-3beta phosphorylation. This may indicate an involvement of the mitochondria in the action of zinc. The effect of zinc on mitochondrial GSK-3beta phosphorylation was not altered by the mitochondrial ATP-sensitive K+ channel blocker 5-hydroxydecanoic acid. Zinc applied at reperfusion reduced cell death in cells subjected to simulated ischemia/reperfusion, indicating that zinc can prevent reperfusion injury. However, zinc was not able to exert protection in cells transfected with the constitutively active GSK-3beta (GSK-3beta-S9A-HA) mutant, suggesting that zinc prevents reperfusion injury by inactivating GSK-3beta. Cells transfected with the catalytically inactive GSK-3beta (GSK-3beta-KM-HA) also revealed a significant decrease in cell death, strongly supporting the essential role of GSK-3beta inactivation in cardioprotection. Moreover, zinc prevented oxidant-induced mPTP opening through the inhibition of GSK-3beta. Taken together, these data suggest that zinc prevents reperfusion injury by modulating the mPTP opening through the inactivation of GSK-3beta. The PI3K/Akt signaling pathway is responsible for the inactivation of GSK-3beta by zinc.
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PMID:Exogenous zinc protects cardiac cells from reperfusion injury by targeting mitochondrial permeability transition pore through inactivation of glycogen synthase kinase-3beta. 1911 35

PKG activator 8-(4-chlorophenylthio)-guanosine 3',5'-cyclic monophosphate (CPT) at reperfusion protects ischemic hearts, but the mechanism is unknown. We recently proposed that in preconditioned hearts PKC lowers the threshold for adenosine to initiate signaling from low-affinity A2b receptors during early reperfusion thus allowing endogenous adenosine to activate survival kinases phosphatidylinositol 3-kinase (PI3K) and ERK. We tested whether CPT might also sensitize A2b receptors to adenosine. CPT (10 microM) during the first minutes of reperfusion markedly reduced infarction in isolated rabbit hearts undergoing 30-min regional ischemia/2-h reperfusion, and salvage was blocked by MRS 1754, an A2b-selective antagonist. Coadministration of wortmannin (PI3K inhibitor) or PD-98059 (MEK1/2 and therefore ERK1/2 inhibitor) also blocked protection. In nonischemic hearts, 10-min infusion of CPT did not change phosphorylation of Akt or ERK1/2. Neither did a subthreshold dose (2.5 nM) of the nonselective but A2b-potent receptor agonist 5'-(N-ethylcarboxamido)adenosine (NECA). However, when 2.5 nM NECA was combined with 10 microM CPT, both phospho-Akt and phospho-ERK1/2 significantly increased, indicating CPT had lowered the threshold for A2b-dependent signaling. The PKC antagonist chelerythrine blocked this phosphorylation induced by CPT + NECA. Chelerythrine also blocked the anti-infarct effect of CPT as did nonselective (glibenclamide) and mitochondrial-selective (5-hydroxydecanoate) K(ATP) channel blockers. A free radical scavenger, N-(2-mercaptopropionyl)glycine, also blocked CPT protection. We propose CPT targets PKG, which activates PKC through mitochondrial K(ATP) channel (mitoKATP)-dependent redox signaling, a sequence mimicking that already documented in preconditioning. Activated PKC then augments sensitivity of normally low-affinity cardiac adenosine A2b receptors so endogenous adenosine can protect by activating Akt and ERK.
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PMID:Infarct limitation by a protein kinase G activator at reperfusion in rabbit hearts is dependent on sensitizing the heart to A2b agonists by protein kinase C. 1866 Apr 52

Ischemic preconditioning (IPC) is a potent cellular protective mechanism whereby brief periods of sublethal ischemia protect the myocardium from prolonged ischemia-induced injury. We demonstrate the selective role of phosphatidylinositol 3-kinase (PI3K) isoforms in IPC. Hearts from PI3Kgamma knockout mice (PI3Kgamma(-/-)) displayed poorer functional recovery and greater tissue injury following IPC compared to wild-type and PI3Kgamma(+/-) hearts. Examination of the cell-signaling pathways revealed restored phosphorylation levels of Akt and glycogen synthase kinase (GSK)3beta in wild-type hearts, which were abolished in PI3Kgamma(-/-) hearts subjected to IPC. Inhibition of GSK3beta by LiCl reversed the loss in protection in PI3Kgamma(-/-) hearts. In contrast, mice expressing a cardiac-specific kinase-deleted PI3Kalpha (PI3KalphaDN) were resistant to injury induced by 30 minutes of ischemia followed by 40 minutes of reperfusion. Furthermore, the resistance of PI3KalphaDN hearts to ischemia/reperfusion correlated with the persistent expression of p110gamma and was blocked by the PI3K inhibitor wortmannin, suggesting the possible enhanced cell signaling through the PI3Kgamma pathway. These results demonstrate the importance of the PI3Kgamma-Akt-GSK3beta signaling pathway in IPC. Selective activation of myocardial PI3Kgamma may be an attractive target for the treatment of ischemic heart disease.
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PMID:Phosphatidylinositol 3-kinase gamma is a critical mediator of myocardial ischemic and adenosine-mediated preconditioning. 1868 45

Calcineurin (CaN) is a calcium/calmodulin-dependent protein phosphatase that has an important role in ischemia-induced apoptosis. The serine/threonine kinase, Akt, which is also known as protein kinase B, has an important role in the cell death/survival pathways. Akt is activated by its phosphorylation, which is positively regulated by phosphatidylinositol 3-kinase (PI3K) and negatively regulated by a class of protein phosphatases (PPs) in tissue. However, the relationship between CaN and Akt after transient ischemia remains unclear. In the present study, we investigated whether CaN is involved in neuronal cell apoptosis and Akt dephosphorylation that occur during ischemic injury. We examined the interdependence between CaN and Akt/protein kinase B (PKB) in the rat retina after transient ischemia. After ischemic damage, we detected changes in levels of CaN, Akt and Bad in rats in the presence or absence FK506, CaN inhibitor. Our results show that CaN cleavage reduced Akt phosphorylation at Thr308 and Ser473, and led to apoptosis via dephosphorylation of the proapoptotic Bcl-2 family member Bad. After treatment with FK506, Akt and Bad dephosphorylation was greatly reduced. The total number of TUNEL-positive neurons was reduced by intravitreal injection of FK506 after transient ischemia. These results indicate that CaN cleavage negatively regulates Akt phosphorylation and is involved in retinal cell apoptosis after transient ischemia.
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PMID:Calcineurin mediates AKT dephosphorylation in the ischemic rat retina. 1870 31

Postconditioning (POC), a novel strategy of cardioprotection against ischemia-reperfusion injury, is clinically attractive because of its therapeutic application at the predictable onset of reperfusion. POC activates several intracellular kinase signaling pathways, including phosphatidylinositol 3-kinase (PI3K)-Akt (RISK). The regulation of POC-induced survival kinase signaling, however, has not been fully characterized. JAK-STAT activation is integral to cardiac ischemic tolerance and may provide upstream regulation of RISK. We hypothesized that POC requires the activation of both JAK-STAT and RISK signaling. Langendorff-perfused mouse hearts were subjected to 30 min of global ischemia and 40 min of reperfusion, with or without POC immediately after ischemia. A separate group of POC hearts was treated with AG 490, a JAK2 inhibitor, Stattic, a specific STAT3 inhibitor, or LY-294002, a PI3K inhibitor, at the onset of reperfusion. Cardiomyocyte-specific STAT3 knockout (KO) hearts were also subjected to non-POC or POC protocols. Myocardial performance (+dP/dt(max), mmHg/s) was assessed throughout each perfusion protocol. Phosphorylated (p-) STAT3 and Akt expression was analyzed by Western immunoblotting. POC enhanced myocardial functional recovery and increased expression of p-STAT3 and p-Akt. JAK-STAT inhibition abrogated POC-induced functional protection. STAT3 inhibition decreased expression of both p-STAT3 and p-Akt. PI3K inhibition also attenuated POC-induced cardioprotection and reduced p-Akt expression but had no effect on STAT3 phosphorylation. Interestingly, STAT3 KO hearts undergoing POC exhibited improved ischemic tolerance compared with KO non-POC hearts. POC induces myocardial functional protection by activating the RISK pathway. JAK-STAT signaling, however, is insufficient for effective POC without PI3K-Akt activation.
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PMID:Regulating RISK: a role for JAK-STAT signaling in postconditioning? 1870 42


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